1. Field of the Invention
The present invention relates to a protein which induces apoptosis (cell death), a gene encoding the same, and a therapeutic agent for malignant tumors.
2. Background Art
The mitogen-activated protein (MAP) kinase signaling cascade, a signal transduction pathway well conserved in cells from yeasts to vertebrates, consists of three distinct members of the protein kinase family, including MAP kinase (MAPK), MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK) (T. Sturgill & J. Wu, Biochim. Biophys. Acta. 1092, 350, 1991; E. Nishida & Y. Gotoh, Trends Biochem. Sci., 18, 128, 1993; B. Errede & D. Levin, Curr. Opin. Cell Biol., 5, 254, 1993; C. Marshall, Curr. Opin. Genet. Dev., 4, 82, 1994). MAPKKK phosphorylates and thereby activates MAPKK, and the activated form of MAPKK in turn phosphorylates and activates MAPK. Activated MAPK translocates to the cell nucleus and regulates the activities of transcription factors and thereby controls expression of various genes (T. Sturgill & J. Wu, Biochim. Biophys. Acta, 1092, 350, 1991; E. Nishida & Y. Gotoh, Trends Biochem. Sci., 18, 128, 1993; B. Errede & D. Levin, Curr. Opin. Cell Biol., 5, 254, 1993; C. Marshall, Curr. Opin. Genet. Dev., 4, 82, 1994).
Recent studies on MAPK signal transduction pathways have shown that at least two distinct MAPKKK-MAPKK-MAPK signal transduction pathways function in mammalian cells (R. Davis, Trends Biochem. Sci., 19, 470, 1994; A. Waskiewicz & J. Cooper, Curr. Opin. Cell Biol., 7, 798, 1995; J. Kyriakis & J. Avruch, J. Biol. Chem., 265, 17355, 1990; B. Derijard et al., Cell, 76, 1025, 1994; M. Yan et al., Nature, 372, 798, 1994; K. Yamaguchi et al., Science, 270, 2008, 1995; J. Kyriakis et al., Nature, 369, 156, 1994; I. Sanchez et al., Nature, 372, 794, 1994; B.
Derijard et al. Science, 267, 682, 1995; S. Matsuda et al., J.
Biol. Chem., 270, 12781, 1995). These two pathways each consist of the Raf-MAPKK-MAPK pathway and the MEKK-SEK1 (or MKK4)-SAPK (or JNK) pathway.
MKK3/MAPKK6 (or MKK6, a close relative of MKK3) and p38 protein kinase are protein kinases corresponding to MAPKK and MAPK, respectively, and are known to form another MAPK signal transduction pathway (R. Davis, Trends Biochem. Sci., 19, 470, 1994; A. Waskiewicz & J. Cooper, Curr. Opin. Cell Biol., 7, 798, 1995; J. Han et al., J. Biol. Chem., 271, 2886, 1996; J. Raingeaud et al., Mol. Cell. Biol., 16, 1247, 1996; T. Moriguchi et al., J. Biol. Chem., 271, 13675, 1996).
Recent studies suggest that the SAPK and/or p38 MAP kinase signaling cascades are involved in at least a part of the signal transduction pathways which induce apoptosis (Z. Xia et al., Science, 270, 1326, 1995; Y. -R. Chen et al., J. Biol. Chem., 271, 631, 1996; N. Johnson et al., J. Biol. Chem., 271, 3229, 1996; M. Verheij et al., Nature, 380, 75, 1996). Apoptosis herein means cell death different from necrosis, namely program cell death. In apoptosis, DNA in each nucleosome is fragmented and the fragmented DNAs can be observed like a ladder by electrophoresis. Furthermore, apoptosis is considered to be involved in autoimmune diseases, HIV infection, neurotic diseases, hepatitis, leukemia, renal diseases, skin diseases, eye diseases and aging as well as cancer degeneration ("Forefront of Research on Apoptosis." Ed. Masayuki Miura, Shigenobu Toya and Sadatoshi Kizaki, Experimental Medicine, Vol. 13, 1995).
Tumor necrosis factor-.alpha. (TNF-.alpha.) is known to be a strong cellular apoptosis initiation substance. A recent study has shown that such cellular apoptosis initiation substances activate the SAPK signal transduction system (J. Kyriakis et al., Nature, 372, 794, 1994; J. Raingeaud et al., J. Biol. Chem., 270, 7420, 1995).
However, as far as the inventors know, proteins corresponding to MAPKKK present in upstream of the MKK3-p38 pathway and the SEK1-SAPK pathway, mechanisms of activation of these pathways, and mechanisms of apoptosis through these pathways have not been reprted.